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Stroke and Neuroprotection
Stroke: Definition
A syndrome characterized by acute onset of a neurologic
deficit that persists for at least 24 hours, reflects focal
involvement of the central nervous system, and is the result
of a disturbance of the cerebral circulation.
Stroke : A silent epidemic
• Stroke the second leading cause of death and major cause of
disability worldwide1,2
• Two-thirds of stroke deaths occur in developing countries1,2
• In India, the incidence and 30 day case fatality rates are
higher than that in developed countries3,4
• Significant increase in noncommunicable diseases such as
stroke and CAD in both urban and rural India2
1. .Donnan GA, Fisher M, et al, Lancet 2008;371:1612-232. .Pandian JD, Srikanth V, et al, Stroke 2007;38:3063-93. .Das K, Banerjee TK, et al, Stroke 2007;38:906-104. .Dalal P, Bhattacharjee M, et al, Indian Acad Nerolol 2007;10:130-6
Stroke in India
• During the last decade, the age-adjusted prevalence rate of
stroke was between 250-350/100,000.
• Recent studies showed that the age-adjusted annual
incidence rate was 105/100,000 in the urban community of
Kolkata and 262/100,000 in a rural community of Bengal.
• The ratio of cerebral infarct to hemorrhage was 2.21.
• Hypertension was the most important risk factor.
• Stroke represented 1.2% of total deaths in India.
Epidemiology of stroke in India, Tapas KumarNeurology Asia 2006; 11 : 1 – 4
Stroke types and incidence:
National Stroke Association developed
the following guidelines to help people reduce their risk for stroke…
Up to 80% of strokes are preventable!Up to 80% of strokes are preventable!
Etiology
• Complication of several disorders
• Atherosclerosis – most common.
• Hypertension, smoking, diabetes.
• Heart disease – Atrial fibrillation.
• Other: – Trauma – fat embolism
– Tumor, Infection
Risk Factors
• Heart disease
• Arrhythmias
• Diabetes Mellitus
• Smoking
• Obesity
• Transient ischemic attacks (TIA’s)
Ischaemic cascade
Ischaemic brain injury results from a cascade
Starts with energy depletion leading to cell death
Reduced blood supply causes starving of neurons
Failure of mitochondria to produce ATP
ATP dependent ion channels stop functioning
Neurons depolarize,allowing excess entry of calcium and
sodium
Excess glutamate release from synaptic terminals
Pathophysiology - Stroke
Excess glutamate causes neurotoxicity
Release of inflammatory substances from clot causes cell membrane damage
Free radicals produced by membrane lipid degradation and mitochondrial injury
Free radicals cause destruction of cell membrane & other vital functions of cell
Pathophysiology- Stroke
Pathophysiology- stroke
Neurons in the penumbra may
benefit from neuroprotection
before and after reperfusion
Reperfusion-induced oxidative stress is accompanied by deterioration of brainMitochondria1
Mediators of inflammation, cytokines, such as platelet-activating factor, interleukin-1(IL-1), and tumor necrosis factor β, are produced by injured brain cells2
Nitric oxide and oxidative stress are linked to DNA damage and activation of poly(ADPribose) polymerase, a nuclear enzyme that facilitates DNA repair and regulates transcription3
Pathophysiology
1. Schild L, FEBS J. 2005;272(14):3593-601. 2. Dirnagl U, Trends Neurosci. 1999;22(9):391-7.3. Lo EH, Nat Rev Neurosci. 2003;4(5):399-415.
• Cell damage leads to cell death
There is evidence that free radicals
and peroxynitrate can cause cell
damage1
• The important role of oxygen
freeradicals in cell damage
associated with stroke is
underscored by the fact that even
delayed treatment with free-radical
scavengers can be effective in
experimental focal cerebral
ischemia2
• In milder ischemic injury, cell death
resembles apoptosis (cell suicide),
particularly within the ischemic1. Lipton P. Ischemic cell death in brain neurons. Physiological Reviews. Oct 1999;vol. 79; 1431-1568. 2. Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke:an integrated view. Trends Neurosci. 1999;22(9):391-7.
Pathophysiology
Immediate Treatment Options
Thrombolysis (tPA) Aspirin Antiplatelet agents Fluids “Blood Thinner” (heparin) Neuroprotection: new option
Management of ischaemic stroke
• Stroke treatment shown rapid advances over last decade or so
• Proven therapies include IV thrombolytics, use of aspirin within 48 hrs and decompressive surgery for malignant MCA infarction1
• Secondary prevention measures include antiplatelets, anticoagulants, cholesterol reduction1
1. .Donnan GA, Fisher M, et al, Lancet 2008;371:1612-232. Brainin M, Teuschl Y, et al, Lancet Neurol 2007;6:533-61,
Rapid diagnosis, implementation of early preventive treatment, early recognition of
complications and mobilization improve overall outcomes2
• Intravenous thrombolysis with rtPA within 3 hrs of symptom onset, currently approved for management of acute ischaemic stroke
• It improves rates of favorable outcome
• Patients with mild to moderate strokes, younger persons and those treated very early have best chances for favourable outcome
P. N. Sylaja,Ann Indian Acad Neurol 2008;11:S24-S29
Intravenous thrombolysisA Potent Weapon
• Small percentage of patients receive rtPA
• Narrow inclusion criteria within 3 hrs and multiple exclusion limits the use of rtPA
• IV rtPA given alone produces recanalization in about 50% of patients*
• Major hindrance to thrombolytic therapy is delay in patients reaching hospital
• Healthcare infrastructure poor in rural areas
• Access to and affordability of investigation and treatment are major concern
Intravenous thrombolysisLimitations
P. N. Sylaja,Ann Indian Acad Neurol 2008;11:S24-S29* - Jose Suarez, Ann Indian Acad Neurol 2008;11:S30-38
• Alternative approaches to IV thrombolytic administration have been explored
• IA rtPA or streptokinase or a combination of IV rtPA within 3 hrs and followed by IA rtPA are being used
• Therapeutic time window is expanded
• However, time to treatment for IA thrombolysis is longer compared to IV
• Limitations: Need to assemble angiography team, confirm occlusion, risk of invasive technique and also cost of treatment
Intra-arterial thrombolysisAlternative/ Additional approach
Jose Suarez, Ann Indian Acad Neurol 2008;11:S30-38
• Patients with large cortical or cerebellar infarctions are at high risk of developing malignant cytotoxic edema
• Peak of brain edema typically occurs at day 2 to 7, but can occur as late as day 14
• Medical treatment includes mannitol or hypertonic saline• However, the anti-edematous effect of these agents are based
on osmosis principle only
Infarct related edema
David S, Stephan M, Clin Chest Med 30 (2009) 103-122
Neuroprotection in Stroke
Neuroprotection
• Neuroprotection is the mechanisms and strategies used to protect against neuronal injury or degeneration in the Central Nervous System (CNS) following acute disorders (e.g. stroke or nervous system injury/trauma) or as a result of chronic neurodegenerative diseases (e.g. Parkinson's, Alzheimer's, Multiple Sclerosis).
ISCHEMIC PENUMBRA
• In the area of ischemia, there is a CENTRAL CORE with marked reduction in CBF and a surrounding area of marginal blood flow called the ‘ISCHEMIC PENUMBRA’.
• Ischaemic penumbra is “ischaemic tissue which is functionally impaired and is at risk of infarction and has the potential to be salvaged by reperfusion and/or other strategies.
• The ischemic area becomes perfusion dependent and any decrease in systemic blood pressure can extend the area of ischemia and infarction. In the penumbra, there is a moderate ischemia.
CORE ISCHEMIC AREA (CBF<25% OF NORMAL
PENUMBRA (CBF ~ 25 – 50% OF NORMAL)
The penumbral concept
(1) penumbral tissue is an area of hypoperfused, abnormal tissue with physiological and biochemical characteristics, or both, consistent with cellular dysfunction but not cellular death;
(2) the tissue is within the same ischemic territory as the infarct core;
(3) the tissue can either survive or progress to necrosis; and (4) salvage of the tissue is associated with better clinical
outcome.
If it is not salvaged this tissue is progressively recruited into the infarct core which will expand with time into the maximal
volume originally at risk”Lancet 2009; 8: 261-69
Neuronal protective agents
• Any agent or drug that protects the brain from secondary injury caused by stroke.
NEUROPROTECTANTS
Hypothermia , powerful neuroprotective option but not well studied in stroke treatment
Nimodipine, several studies regarding nimodipine in stroke, with some confliciting results.
• NMDA receptor antagonists : e.g. : Dextrorphan, Selfotel (Higher mortality in selfotel group at 30 days (p<.05), and more behavioral effects, Stroke 2000;31(2):347-54)
• Nitric oxide synthetase inhibitor: e.g : Lubeluzole, poor efficacy as measured by barthel index, Stroke 1997;28:2338-2346
• Anti-adhesion antibodies : e.g. : Enlimomab (mortality and Rankin score worse in enlimomab administered patients, Neurology 1997;48(Supp) A270
• Above agents failed to show satisfactory results (serious adverse effects and lack of efficacy) except
• NEURONAL MEMBRANE STABILIZERS : Citicholine • FREE RADICAL SCAVENGERS : EDARAVONE
Role of Edaravone in the management of Acute Ischaemic Stroke
• Free radicals play crucial role in ischaemic brain injury
• Exacerbate membrane damage through peroxidation of unsaturated fatty acids leading to neuronal death and brain edema
• Physiological systems involved in removal of free radicals are impaired and formation of free radicals is further increased
Rationale for neuroprotection
Hiroshi Yoshida, hidekatsu Yanai, et al, CNS Drugs Reviews, Vol 12, Number 1, pp 9-20, 2006
Scavenging free radicals and prevention of lipid peroxidation can directly suppress
brain edema
• Edaravone , a novel free radical scavenger protects neurons by inhibiting vascular endothelial injury and by ameliorating neuronal damage caused by brain edema
• Edaravone inhibits both nonenzymatic lipid peroxidation and lipooxygenase pathway
• Potent antioxidant effects against ischaemia/reperfusion-induced vascular endothelial cell injury, delays neuronal death, brain edema and consequently lessens the neurological deficits
Neuroprotection: Role of Edaravone
Hiroshi Yoshida, hidekatsu Yanai, et al, CNS Drugs Reviews, Vol 12, Number 1, pp 9-20, 2006
Cerebral ischaemia Reperfusion
Excessive inflow of oxygen
H2O2
Deterioration of cerebral infarction with exacerbated symptoms
Increased infarct volume
Delayed neutrocytes necrosis
Neurological symptoms
Brain edema
Free radical production OH- Hydroxyl
Neurocyte injury
Cell membrane injury
Vascular endothelial injury
Activation of arachidonic cascade
Phospholipase A2
Free radical productionO2-(superoxide)
Adapted from Hiroshi Yoshida, hidekatsu Yanai, et al, CNS Drugs Reviews, Vol 12, Number 1, pp 9-20, 2006
Edaravone
Neuroprotection: Role of Edaravone
• Edaravone can inhibit peroxidation of membrane lipids initiated by water soluble and lipid solouble radicals
• Edaravone is a low molecular wt radical scavenger which has a BBB permeability of 60% unlike Superoxide dismutase which has a difficulty in entering the BBB
• Edaravone, after administration eliminates highly toxic hydroxyl radicals, preferentially in ischemic penumbra
• Edaravone does not affect blood coagulation, platelet aggregation, fibrinolysis or bleeding time, hence there is no risk of additional bleeding
H. Tohgi, K. Kogure, et al, Cerebrovascular Dis 2003;15:222-229
Neuroprotective effects of Edaravone in cerebrovascular injury
Edaravone in acute brain infarction
A multicenter, randomized, placebo controlled, double blind trial conducted to verify its therapeutic efficacy in ischaemic stroke
N=250 (both thrombotic and embolic types), Edaravone - 125 patients; Placebo - 125 patients
Edaravone given within 72 hrs of onset of stroke at the dose of 30 mg, BID for 14 days
Fibrinolytic agents (urokinase, rtPA, ozagrel and citicoline) avoided throughout the study
H. Tohgi, K. Kogure, et al, Cerebrovascular Dis 2003;15:222-229
Edaravone in acute brain infarction
Functional outcome measured at 3 months or at discharge within three months using Modified Rankin Scale
Additionally outcome data collected at 3, 6 and 12 months Results – Significant difference between two groups in favour
of Edaravone group in terms of functional outcome (p=0.03) Improvement in functional outcome sustained for relatively
longer time Better clinical outcome when given within 24 hrs of symptom
onset
H. Tohgi, K. Kogure, et al, Cerebrovascular Dis 2003;15:222-229
Effect of novel free radical scavenger, edaravone on acute brain infarction
H. Tohgi, K. Kogure, et al, Cerebrovascular Dis 2003;15:222-229
76
52
N=250 (both thrombotic and embolic types) ,edaravone (30 mg, BID for 14 days) given to 125 patients and placebo to 125
Edaravone : beneficial in combination therapy with fibrinolytic agents , leading to expansion of therapeutic time window
Edaravone in internal carotid artery occlusion
Therapeutic effect of Edaravone was evaluated in patients with severe carotid artery stroke
Patients (baseline NIHSS score =/> 15) were treated with Edaravone for 14 days (n=30) and compared with historical control cohort of similar patients (n=31)*
Infarct volume on CT performed on day 2 in Edaravone group were smaller than those without Edaravone (p<0.02)
Hemorrhagic transformation of infarct on day 2 was less severe in Edaravone group compared to without it (p<0.03)
Kazunori Toyoda, Kenichiro Fujii,et al, Journal of the Neurological Sciences 221 (2004) 11-17
*10% Glycerol to all, rtPA, Heparin at discretion
Edaravone in patients with internal carotid artery occlusion
Kazunori Toyoda, Kenichiro Fujii,et al, Journal of the Neurological Sciences 221 (2004) 11-17
Edaravone was associated with delayed evolution of infarcts and edema in patients with severe carotid artery stroke and decreased mortality during acute stage
Effect of Edaravone on ischaemic cerebral edema assessed by MRI
T2-weigted MRI can both visualize and quantify vasogenic
edema therefore it is an important method to assess efficacy of therapies for stroke
Antiedema effect of Edaravone was evaluated in patients with extensive hemispheric ischaemic stroke
T2 relaxation time was calculated in the infarct core, boundary
zone of infarct and T2 mapping was performed before and after
edaravone treatment
Edaravone administration significantly decreased the mean T2 –
relaxation time in the boundary zone of infarct (p=0.008)
Conclusion – Edaravone can salvage the boundary zone of the infarct and is a useful cytoprotective antiedema agent
Satoshi Suda , Hironaka Igarashi, et al, Neurol. Med Chir (Tokyo) 47, 197-202,2007
Edaravone diminishes free radicals from circulating neutrophils in patients with
ischaemic stroke
Study investigated effects of Edaravone on oxidative stress markers of circulating neutrophils in patients with ischaemic stroke
Edaravone 30mg – 21 patients; Ozagrel 40mg (thromboxane A2
synthase inhibitor) – 19 patients Intracellular reactive oxygen species of neutrophils were
measured by chemiluminescence assay Edaravone significantly decreased the intracellular reactive
oxygen species of neutrophils Conclusion – Reduction of intracellular reactive oxygen species
and suppression of superoxide production may be responsible for clinical efficacy of edaravone in patients with ischaemic stroke
Hitoshi Aizawa, Yoshiniro Makita, et al, Internal Medicine , doi:10.2169/internal medicine . 45.1491
Efficacy of edaravone for the treatment of Acute Lacunar Infarction
Retrospective analysis of 70 patients with lacunar infarct admitted within 24 hrs of stroke onset, who were given Edaravone treatment in addition to routine treatment
Clinical status at baseline assessed using NIHSS score Modified Rankin Scale (MRS) used to assess clinical outcome at 3
months (good outcome defined as MRS =/<2) Routine treatment was continued (IV heparin, glycerol, ozagrel
sodium, oral antiplatelet drugs like aspirin, ticlopidine)
M. Mishira, Y. Komaba, et al , Neurol Med Chir (Tokyo) 45, 344-348, 2005
Efficacy of edaravone for the treatment of Acute Lacunar Infarction
Edaravone added to conventional treatment (14 days) 70% of patients had a good outcome with MRS score =/<2 Higher baseline NIHSS score and higher age adversely
affected outcome After adjustment for this effect, the results still indicated that
Edaravone significantly improved functional outcome
M. Mishira, Y. Komaba, et al , Neurol Med Chir (Tokyo) 45, 344-348, 2005
Conclusion – Edaravone is a promising free radical scavenger for the treatment of patients with acute
lacunar stroke
Edaravone in patients with traumatic brain injury (TBI)
Lipid peroxidation caused by reactive oxygen species is involved in traumatic brain injury (TBI)
Therapeutic strategy for TBI involves control of lipid peroxidation
Present study used in vitro & ex vivo techniques to study whether Edaravone can scavenge alkoxyl radicals (OR-)
Jugular venous blood collected from 17 TBI patients immediately before and 20 min after Edaravone administration
Keneji Dohi, Kazue satoh, et al, Journal of Neurotrauma, Volume 23, Number 11, 2006, pp. 1591-1599
Higher OR- levels in blood of untreated patients than in normal control
Treatment with edaravone suppresses OR- level by 24.6%
Conclusion – Edaravone may be useful for preventing lipid peroxidation in patients with TBI
Keneji Dohi, Kazue satoh, et al, Journal of Neurotrauma, Volume 23, Number 11, 2006, pp. 1591-1599
Edaravone in patients with traumatic brain injury (TBI)
Diminishes Free Radicals from Circulating Neutrophils in Ischemic Brain Attack
Amount of superoxide produced by neutrophils stimulated byphorbol myristate acetat (PMA) before and after treatmentwith edaravone or ozagrel
The superoxideproduction by neutrophils decreased after treatment with edaravone in patients with ischemic brain attack (Wilcoxontest, p=0.001)
2006 The Japanese Society of Internal Medicine
IV Inj. Edaravone 30 mg for 10 min before myocardial reperfusion decreasedSerum CK-MB and improved left ventricular ejection fraction in pts with
Acute MI
Edaravone in Acute Myocardial Infarct
Recent Patents on Cardiovascular Drug Discovery, 2006, Vol. 1, No. 1 89
Clinical Evidence in CEA
• Pretreatment with edaravone can prevent development of cognitive impairment after carotid endarterectomy (CEA). |Surg Neurol. 2005 Oct;64(4):309-13
• In patients with cortical infarcts, edaravone reduced oxidative damage, thereby limiting the degree of brain damage, as measured by plasma biomarkers. Free Radic Biol Med. 2005 Oct 15;39(8):1109-16.
Edaravone – new clinical data
• Edaravone dose-dependently increases rehabilitation gain according to DeltaFIM-
M and DeltaBI scores in patients with cardioembolic stroke. Clin Drug Investig.
2010;30(3):143-55
• Edaravone significantly reduced oxidative cell death in both neuronal cells and
primary rat astrocytes and thus protects component of neurovascular unit. Brain
Res. 2010 Jan 11;1307:22-7
• Edaravone inhibited production of free radicals known to induce neuronal
degeneration and cell death after brain injury, with the potential to differentiate
into neurons and glia around the area damaged by TBI. Neurotox Res. 2009
Nov;16(4):378-89.
Citicoline in Stroke
Rationale for citicoline
• Precursor of phosphatidylcholine, a vital component of neuronal membrane.
• Reduces the dysfunction of BBB, decreases cerebral edema, activates cerebral energy metabolism.
• Provides the cytidine & choline. Choline is essential for the synthesis of Acetylcholine (the cholinergic neurotransmitter)
• Inhibits Phospholipase A2 thereby :– preserves neuronal membrane integrity– promotes neuronal membrane repair– inhibits the release of free fatty acids & ARA – inhibits free radical damage
J our Of Neurochemistry, 2002,80,12-23
Jour Of NeuroSci Res, 2002, 70:133-9
Effect of citicoline
A. Normal synthesis of phophotidylcholine
B. Effect of Ischemia
C. Reversal of increased FFA with citicoline
Clinical efficacy
Since 1980’s , 13 trials have been done with citicoline in stroke management
9 in Europe & Japan, 4 in the U.S. European trials showed citicoline improved global & neurological
function , earlier motor & cognitive recovery Large multicenter studies in Japan showed citicoline improved global
outcome rating scale However, subsequent analysis showed citicoline treatment for 6
weeks improved overall recovery at week 12
A comparative, randomized study evaluated efficacy of citicoline N = 80 (>65 years, in acute phase of ischemic stroke) Mild to moderate impaired consciousness with a score of >10 on GCS
(Glasgow coma scale) Equal no. of patients received citicoline & control Dose – Citicoline 1g/8hrs as a daily dose for 10 days Citicoline showed significant improvement in GCS score (12.55 to 13.85)
Citicoline in acute cerebrovascular disease
Julio J et al, Citicoline: Pharmacological and Clinical Review, 2006 Update,Methods Find Exp Clin Pharmacol 2006, 28(Suppl. B): 1
.
(Significant improvement in GCS scores)
Citicoline in acute cerebrovascular disease
Julio J et al, Citicoline: Pharmacological and Clinical Review, 2006 Update,Methods Find Exp Clin Pharmacol 2006, 28(Suppl. B): 1.
Significant decrease in lesion volume by 17.2 cc compared to placebo by 6.9 cc at 12 weeks as measured by MRI.
Placebo citicoline
Citicoline in acute cerebrovascular disease
N=100 Citicoline 500mg/day (oral) for 6 weeks.
Expert Opinion on Pharmacotherapy, Volume 10, Number 5, April 2009 , pp. 839-846(8)
Citicoline in HEAD INJURY
• Accelerates the recovery of neurological symptoms
• Accelerates the resolution of brain edema on CT
• Reduces hospital stay
• Better quality in the evolution
• Improves the global functional outcome
• Reduces the post-concussional syndrome
Citicoline in head trauma
A double blind ,placebo controlled study involving 60 patients with severs head trauma
Citicoline 750mg/day (IV) – 6 days Citicoline 750mg/day (IM) – 20 days Clinical evaluation was continued for upto 6 months.
Observations Response to painful stimuli superior in citicoline group at
day 15 compared to placebo (p<0.01) Greater recovery from neurological deficits observed in
citicoline group Autonomous ambulation was seen in 84% of patients in
citicoline grp compared to 62.5 in placebo at 120 days Difference statistically significant from day 60 (p<0.01)
Julio J et al, Citicoline: Pharmacological and Clinical Review, 2006 Update,Methods Find Exp Clin Pharmacol 2006, 28(Suppl. B): 1.
(Number of patients showing normalization of state of consciousness in relation to time and treatment)
Citicoline in head trauma
N=100 p=<0.05
Response to painful stimuli superior in citicoline group at day 15 Greater recovery from neurological deficits and Autonomous ambulation was seen in 84% of patients in citicoline grp
(Significantly less % of patients showing neurological complications with citicoline
Citicoline in head trauma
Clinical data –citicoline in stroke
In a double blind, multicenter (63 Japanese Academic centers),
placebo controlled study in 272 patients with stroke given citicoline
1g/day/14 days (IV) -- effective and safe drug for the treatment of
acute cerebral infarction. (Stroke. 1988;19:211-216)
• A multicenter, DB controlled trial, conducted by the Citicoline Stroke
Study Group (N=259) examined the effects of oral citicoline(500mg;
1,000 mg; or 2,000 mg) after 12 weeks showed that citicoline pts
have twice the chance of stroke recovery compared to patients on
placebo. (Neurology 1997;49:671-78)
Clinical data –citicoline in stroke
Meta-analysis of 4 large trial done in the U.S.-- citicoline
treatment showed significant improvement in patients who
had achieved an almost complete recovery at 3 months in
daily routine activity and functional activity and is more
effective in patients with moderate to severe acute ischaemic
stroke (Stroke. 2002;33:2850-2857)
• Similarly citicoline found effective if combined with
thromlytic agents in stroke .
Citicoline –New data
• Citicoline in Stroke – citicoline administered within 24h after
moderate to severe stroke is safe and increases the probability of recovery within 3 months- Exp Opin Pharmthr Apr 2009
• Citicoline in Brain Injury CORBIT Trial – Ongoing to complete enrollment by Aug 2010 - J Neurotrauma Dec 2009
• Citicoline widely available agent in Neuroprotection and repair –Meta-analysis of 10 trials enrolling 2279 pts suggests citicoline treatment reduced frequency of death and disability. (Rev Neurol Dis 2008)
Citicoline in Mild Cognitive Impairment
Mild cognitive impairment (MCI) involves slight loss of memory without significant effect on other cognitive functions
Approximately 12% of patients with MCI advance annually to develop Alzheimer’s disease
Meta analysis of 12 clinical trials show Citicoline improves memory Behavior Overall clinical improvement
Hence citicoline may prove effective in age related cognitive decline that may be a precursor of dementia
Citicoline in Parkinson’s disease
Citicoline shown dopamine agonist properties
Citicoline 600mg/day/10 days (IV) shown improvement in bradykinesia, rigidity & tremors
Allows reduction of levodopa ,hence reduces levodopa related adverse effects
Discontinuation of citicoline worsened symptoms
• New strategies in the management of Parkinson’s disease using a phospholipid precursor (CDP-choline) improvements in bradykinesia and rigidity.
(Neuropsychobiology 1982;8:289-296.)
Thank You